This grant will support continuation and expansion of autopsy research on brain aging, dementia, cognitive decline, Parkinson's disease, and stroke in Japanese American men for whom a wealth of prospectively collected information is available by virtue of their long-standing participation in the Honolulu Heart Program and Honolulu-Asia Aging Study. The principal goal is to improve understanding of the pathologic processes that underlie these illnesses and impairments in late life, and to identify risk factors associated with the brain lesions that represent the essential pathogenic processes. As of March 2005 a total of 615 brain autopsies had been done. This number will increase by approximately 50% over the course of the upcoming 5 years. Analyses to date implicate ischemic cerebrovascular disease as the pathogenic process most frequently linked to dementia in this cohort (25% of cases) and identify multiple microinfarcts as the most specific and consistent indicator. Neurofibrillary tangles (NFT) and/or neuritic plaques (NP) are the dominant or sole lesions associated with dementia in 20% of the demented decedents. Cortical Lewy bodies account for 10%, hippocampal sclerosis for 4%, and mixed (co- dominant) lesions for 18% of the dementia cases. Abnormalities identified in the remaining demented decedents (23%) were limited to generalized atrophy, gliosis, and neuron loss - not implicating a specific pathogenic mechanism. In this population, prevention strategies that reduce the burden of NFT and NP without influencing the other processes would likely have a modest public health impact. Our findings suggest that highly effective prevention programs are likely to require simultaneous targeting of two or more of the underlying processes. Analyses employing neuropathologic lesions as endpoints are conducted in an effort to identify specific risk factors for specific underlying pathogenic processes as an essential preliminary step toward prevention. In addition to accruing additional autopsies, the proposed continuation will support efforts directed toward (1) studies of microvascular ischemic disease, (2) relationships between distributions and densities of microinfarcts and Alzheimer's lesions, (3) relationships between structural characteristics of Circle of Willis arteries and lesions in the brain parenchyma, and (4) identification of the major underlying pathogenic processes responsible for brain atrophy and gliosis, and identification of corresponding risk factors.